This invention relates to novel compounds, pharmaceutical compositions and methods of inhibiting the 5-lipoxygenase pathway of arachidonic acid metabolism in an animal in need thereof which comprises administering to such animal an effective, 5-lipoxygenase pathway inhibiting amount of a 2(3)-(pyridyl)-3(2)-(substituted phenyl)-6,7-dihydro-[5H]-pyrrolo-[1,2-a]imidazole, a 2(3)-(pyridyl)-3(2)-(substituted phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridine or a pharmaceutically acceptable salt thereof.
Davidson et al., U.S. Pat. No. 4,507,481, issued Mar. 26, 1985, disclose compounds of the formula: ##STR2## wherein: X is O or S(O)n;
n is O, 1 or 2; PA1 R.sup.1 is H, lower alkyl, phenyl, benzyl or benzyl substituted with lower alkylamino, lower alkylamino, nitro, halo, hydroxy or lower alkoxy-; PA1 R.sub.2 is H or XR.sup.1 ; PA1 A is CH.sub.2 or CH.sub.2 CH.sub.3 ; PA1 R.sub.3 and R.sub.4 are independently selected from A, lower alkyl, aryl, aryl substituted with lower alkyl, amino, lower alkylamino, nitro, lower alkoxy, hydroxy or halogen; provided that at least one of R.sub.3 and R.sub.4 is aryl or substituted aryl; and PA1 R.sub.5 and R.sub.6 are each H or join to form a double bond at the 2,3-position. PA1 (a) monosubstituted phenyl wherein said substitutent is selected from H, halo, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, C.sub.1-3 alkylsulfinyl, C.sub.1-3 alkylsulfonyl, C.sub.1-3 alkylamino, C.sub.1-3 dialkylamino, CF.sub.3, N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), N-(azacyclo C.sub.5-6 alkyl), prop-2-ene-1-oxy or 2,2,2-trihaloethoxy; PA1 (b) disubstituted phenyl wherein said substituents are the same and are selected from halo, C.sub.1-3 alkoxy, C.sub.1-3 alkyl-amino, C.sub.1-3 dialkylamino, N-(azacyclo C .sub.5-6 alkyl), 2,2,2-trihaloethoxy, prop-2-ene-1-oxy or hydroxy, or the disubstituents together form a methylene dioxy group; or PA1 (c) disubstituted phenyl wherein said substituents are not the same and are independently selected from halo, C.sub.1-3 alkylamino, nitro, N-(C .sub.1-3 alkyl)-N-C.sub.1-3 alkanamido), C .sub.1-3 dialkylamino, amino, or N-(azacyclo C .sub.5-6 alkyl); or PA1 (d) disubstituted phenyl wherein one of said substituents must be C.sub.1-3 alkoxy, hydroxy, 2,2,2-trihaloethoxy or prop-2-ene-1-oxy and the other substituent is independently selected from halo, C.sub.1-3 alkylamino, nitro, N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, amino, or N-(azacyclo C.sub.5-6 alkyl); and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are H, or one or two of R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently selected from H or C.sub.1-2 alkyl; provided that: PA1 (1) when R.sup.1 is 2 or 3-pyridyl and R is monosubstituted phenyl, the substituent selected from other than bromo, iodo, N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), C.sub.1-3 alkylthio, C.sub.1-3 alkylsulfinyl, or C.sub.1-3 alkylsulfonyl; PA1 (2) when R.sup.1 is 2 or 3-pyridyl and R is disubstituted phenyl, the disubstituents are both selected from other than bromo, iodo, amino, hydroxy, nitro, or N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido); PA1 (3) when R is 2, 3 or 4-pyridyl and R.sup.1 is monosubstituted phenyl, the substituent is selected from other than bromo, iodo, N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), C.sub.1-3 alkylthio, C.sub.1-3 alkylsulfinyl, or C.sub.1-3 alkylsulfonyl; and PA1 (4) when R is 2, 3 or 4-pyridyl and R.sup.1 is disubstituted phenyl, the substituents are both selected from other than bromo, iodo, amino, hydroxy, nitro, or N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido); PA1 (a) monosubstituted phenyl wherein said substituent is selected from H, halo, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, C.sub.1-3 alkylsulfinyl, C.sub.1-3 alkyl -sulfonyl, C.sub.1-3 alkylamino, C.sub.1-3 dialkylamino, CF.sub.3, N-(azacyclo C.sub.5-6 alkyl), prop-2-ene-1-oxy or 2,2,2-trihaloethoxy; PA1 (b) disubstituted phenyl wherein said substituents are the same and are selected from halo, C.sub.1-3 alkoxy, C.sub.1-3 alkylamino, C.sub.1-3 dialkylamino, N-(azacyclo C.sub.5-6 alkyl), 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, or the disubstituents together form a methylene dioxy group; PA1 (c) disubstituted phenyl wherein said substituents are not the same and are independently selected from C.sub.1-3 alkylamino, C.sub.1-3 dialkylamino, or N-(azacyclo C.sub.5-6 alkyl); or PA1 (d) disubstituted phenyl wherein one of said substituents must be C.sub.1-3 alkoxy, hydroxy, 2,2,2-trihaloethoxy or prop-2-ene-1-oxy and the other substituent is independently selected from halo, C.sub.1-3 alkylamino, N-(C.sub.1-3 alkyl)-N -(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, amino, or N-(azacyclo C.sub.5-6 alkyl); and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are H, or one or two of R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are independently selected from H or C.sub.1-2 alkyl; provided that: PA1 (1) when R.sup.1 is 2 or 3-pyridyl and R is monosubstituted phenyl, the substituent is selected from other than bromo, iodo, C.sub.1-3 alkylthio, C.sub.1-3 alkylsulfinyl, or C.sub.1-3 alkylsulfonyl; PA1 (2) when R.sup.1 is 2 or 3-pyridyl and R is disubstituted phenyl, the disubstituents are both selected from other than bromo or iodo; PA1 (3) when R is 2, 3 or 4-pyridyl and R.sup.1 is monosubstituted phenyl, the substituents are selected from other than bromo, iodo, C.sub.1-3 alkylthio, C.sub.1-3 alkylsulfinyl, or C.sub.1-3 alkylsulfonyl; and PA1 (4) when R is 2, 3 or 4-pyridyl and R.sup.1 is disubstituted phenyl, the substituents are both selected from other than bromo or iodo; PA1 (a) pyridyl; PA1 (b) monosubstituted phenyl, wherein said substituent is selected from halo, C.sub.1-3 alkoxy, amino, hydroxy, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, C.sub.1-3 alkylamino, C.sub.1-3 dialkylamino, CF.sub.3, N-(C.sub.1-3 alkanamido), N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), N-(azacyclo C.sub.5-6 alkyl), prop-2-ene-1-oxy or 2,2,2-trihaloethoxy; PA1 (c) disubstituted phenyl wherein said substituents are the same and are selected from halo, C.sub.1-3 alkoxy, C.sub.1-3 alkylamino, C.sub.1-3 dialkylamino, amino, N-(azacyclo C.sub.5-6 alkyl), 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, hydroxy, or the disubstituents together form a methylene dioxy group; or PA1 (d) disubstituted phenyl wherein said substituents are not the same and are independently selected from halo, C.sub.1-3 alkylamino, nitro, N-(C.sub.1-3 alkanamido), N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, amino or N-(azacyclo C.sub.5-6 alkyl), and PA1 (e) disubstituted phenyl wherein one of said substituents must be C.sub.1-3 alkoxy, hydroxy, 2,2,2-trihaloethoxy or prop-2-ene-1-oxy and the other substituent is independently selected from halo, C.sub.1-3 alkylamino, nitro, N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, amino, or N-(azacyclo C.sub.5-6 alkyl); PA1 provided that when n is 1, and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are H, X is other than 2,4-dimethoxyphenyl or 4-aminophenyl; PA1 (a) monosubstituted phenyl wherein said substituent is selected from H, halo, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, CF.sub.3 N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, CF.sub.3, N-(azacyclo C.sub.5-6 alkyl), prop-2-ene-1-oxy or 2,2,2-trihaloethoxy; PA1 (b) disubstituted phenyl wherein said substitutents are the same and are selected from halo, C.sub.1-3 alkoxy, C.sub.1-3 dialkylamino, N-(azacyclo C.sub.5-6 alkyl), 2,2,2-trihaloethoxy, or prop-2-ene-1-oxy, or the disubstituents together form a methylene dioxy group; or PA1 (c) disubstituted phenyl wherein said substituents are not the same and are independently selected from halo, nitro, N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, or N-(azacyclo C.sub.5-6 alkyl; or PA1 (d) disubstituted phenyl wherein one of said substituents must be C.sub.1-3 alkoxy, hydroxy, 2,2,2-trihaloethoxy or prop-2-ene-1-oxy and the other substituent is independently selected from halo, C.sub.1-3 alkylamino, nitro, N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, amino, or N-(azacyclo C.sub.5-6 alkyl); PA1 (a) monosubstituted phenyl wherein said substituent is selected from H, fluoro, chloro, C.sub.1-3 alkoxy, C.sub.1-4 alkyl, C.sub.1-3 dialkylamino, CF.sub.3, C.sub.1-3 alkylamino, N-(azacyclo C.sub.5-6 alkyl), prop-2-ene-1-oxy or 2,2,2-trihaloethoxy; PA1 (b) disubstituted phenyl wherein said substituents are the same and are selected from fluoro, chloro, C.sub.1-3 alkoxy, C.sub.1-3 dialkylamino, N-(azacyclo C.sub.5-6 alkyl), 2,2,2-trihaloethoxy, prop-2-ene-1-oxy, or the disubstituents together form a methylene dioxy group; PA1 (c) disubstituted phenyl wherein said substituents are not the same and are independently selected from fluoro, chloro, C.sub.1-3 alkylamino, C.sub.1-3 dialkylamino, or N-(azacyclo C.sub.5-6 alkyl), or PA1 (d) disubstituted phenyl wherein one of said substituents must be C.sub.1-3 alkoxy, 2,2,2-trihaloethoxy or prop-2-ene-1-oxy and the other substituent is independently selected from fluoro, chloro, C.sub.1-3 alkylamino, C.sub.1-3 dialkylamino, or N-(azacyclo C.sub.5-6 alkyl; PA1 (a) pyridyl; PA1 (b) monosubstituted phenyl, wherein said substituent is selected from H, halo, C.sub.1-3 alkoxy, C.sub.1-3 alkylthio, C.sub.1-4 alkyl, N-(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, CF.sub.3, N-(azacyclo C.sub.5-6 alkyl); PA1 (c) disubstituted phenyl wherein said substituents are the same and are selected from halo, C.sub.1-3 alkoxy, N-(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, N-(azacyclo C.sub.5-6 alkyl), or the disubstituents together form a methylene-dioxy group; PA1 (d) disubstituted phenyl wherein said substituents are not the same and are independently selected from halo, nitro, N-(C.sub.1-3 alkanamido), C.sub.1-3 alkoxy, C.sub.1-3 dialkylamino, or N-(azacyclo C.sub.5-6 alkyl); or PA1 (e) disubstituted phenyl wherein one of said substituents must be C.sub.1-3 alkoxy, hydroxy, 2,2,2-trihaloethoxy or prop-2-ene -1-oxy and the other substituent is independently selected from halo, nitro, N-(C.sub.1-3 alkyl)-N-(C.sub.1-3 alkanamido), C.sub.1-3 dialkylamino, or N-(azacyclo C.sub.5-6 alkyl);
Davidson et al. also disclose that such comounds are immunostimulants or immunosuppresants based on (a) their inhibiting or stimulating activity in a chemotaxis assay which measures the ability of a drug substance to influence the movement of murine macrophages responding to complement; (b) their immunosuppressing or activating activity in the Kennedy plaque assay in which an animal's humoral immune system is depressed artificially with 6-mercaptopurine. Neither the chemotaxis assay nor the Kennedy plaque assay is of any known utility for detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. Davidson et al. also disclose that such compounds have antiinflammatory activity as determined by the carrageenan-induced paw edema assay in rats. As stated above, such assay has no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. Davidson et al. also disclose that such compounds have antiviral activity in mice with hepatitis; but such activity is of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.